The neurotrophin family (NGF, NT-3, BDNF and NT-4) and the GDNF family that includes, artemin and neurturin have been shown to be crucial for sensory neuron development. Nociceptors have been shown to be particularly dependent on NGF and GDNF. Preliminary studies from our laboratories show that artemin and neurturin can, like NGF, affect nociceptor survival and responsiveness. These observations have led us to propose the general hypothesis that NGF is required for nociceptor embryogenesis but that during late development, NGF and the GDNF family combine to regulate nociceptor plasticity and phenotype. The goal of this proposal is to test three hypotheses addressing the roles of artemin and neurturin. SA1 tests the hypothesis that neurturin modulates the comprehensive phenotype (CP) of nociceptors. Specificially, we predict that neurturin is important for the development and differentiation of IB4-positive polymodal nociceptors and that it directly affects the heat responsiveness of these neurons. SA2 tests the hypothesis that like NGF, neurturin and artemin can regulate postnatal sensory neuron phenotype and plasticity. We have preliminary data that neurturin and artemin may be even more potent than NGF for sensitizing primary afferents. This is an exciting result as this is the first time that this family of growth factors, that like NGF is made in the targets of sensory neurons, has been shown to alter sensory neuron response properties. SA3 tests the hypothesis that the alterations of primary afferents induced by inflammation are dependent on artemin and neurturin. NGF has been thought to play an important role in inflammatory pain because of its ability to sensitize primary afferents and because it increases during inflammation. Our preliminary data shows that artemin mRNA increases 10-fold more than NGF mRNA 24 hrs after induction of inflammation. In SA3 we will extend these studies and attempt to block inflammatory pain using siRNAs for artemin, neurturin and NGF and their receptors.